Pericytes, mural cells of the kidney peritubular capillaries, have been neglected until recently, and their function in kidney development, homeostasis, pathology and regeneration is only starting to be fully appreciated. In other organs, and also in cancer growth, the crucial role of pericytes in angiogenesis, vessel stabilization and capillary barrier functions is now established. Pericytes provide key molecular signals to endothelium for endothelial migration, growth and stabilization as new vessels. Recent studies from our lab have identified pericytes of the kidney peritubular capillaries as the major myofibroblast precursor, and therefore the cell responsible for fibrogenesis. Kidney injuries lead to pericyte detachment and migration away from peritubular capillaries as cells we call myofibroblasts. New evidence indicates that peritubular capillaries, which have lost pericytes due to this process, are unstable, have impaired barrier function and regress, leading to capillary rarefaction. Therefore capillary rarefaction, which results in organ ischemia, is intrinsically linked fibrogenesis. However pericyte detachment and migration are not necessarily permanent and prevention of detachment or promotion of reattachment may be central to normal organ regeneration. New studies have identified pericyte to endothelial signaling via Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) as a central pathway in regulating pericyte detachment and kidney disease progression. Directly following on from ARRA Challenge Grant funded work and working with a central hypothesis that failure to regenerate peritubular capillaries after injury may lead to interstitial fibrosis and chronic kidney injury wewill undertake the following studies. Aim 1: Using novel genetic ablative methods, determine the function of kidney pericytes in homoeostasis and injury responses in mouse kidney Aim 2. Determine the role of pericyte-derived TIMP3 and ADAMTS1 in regulation of microvascular stability and VEGF receptor signaling Aim 3. Define pericyte-derived VEGFA as a determinant of spontaneous & induced kidney disease progression. PUBLIC HEALTH RELEVANCE: Acute Kidney Injury, Chronic Kidney Disease and End Stage Kidney Disease are major health burdens. Pericytes are cells of the kidney that have recently been descibed to play a major role in kidney disease. In health these cells nurture small blood vessels of the kidney but after injury migrate from the small vessels leading to instability and loss of these precious vessels. These studies will investigate the mechanisms by which pericytes nurture kidney blood vessels and the mechanisms by which they detach in response to injury and thereafter fail to nurture. In understanding these processes we hope to develop new therapies to treat kidney diseases.